This is a Shannon Award providing partial support for the research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon Award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. 5-fluorouracil/leucovorin (5-FU/LV) is considered to be standard postoperative treatment for individuals with metastatic colorectal cancer. This regimen yields a 20-25% objective response rate but does not have a clear impact on survival. Irinotecan (CPT-11) is a water soluble camptothecin analog that inhibits topoisomerase I and has clinical activity against colorectal cancer. We observed a 24% objective response rate in a Phase II clinical trial of irinotecan in patients with 5-FU-refractory colorectal cancer. Others have reported a similar response rate using single agent irinotecan in previously untreated colorectal cancer patients. This suggests that the two regimens are clinically non-cross resistant. Our hypothesis is that a front line regimen integrating both drugs would have significant clinical activity against metastatic colorectal cancer. Previous attempts to combine 5-FU plus/minus leucovorin and irinotecan have been unsuccessful due to unpredictable toxicities and scheduling difficulties. Since there is little preclinical rationale for combining both agents into a single cycle of therapy and since there is no evidence of cumulative toxicity for either, our first specific aim is to conduct a Phase II clinical trial of sequential 5-FU/LV and irinotecan in full doses in patients with newly diagnosed, metastatic colorectal cancer. Should the objective response rate be 40% or greater, a comparative trial against 5-FU/LV would be warranted. Identification of factors that predict for response to this therapy is the second goal of this proposal. Our preliminary data suggest that selected characteristics of the primary tumor may correlate with clinical response to 5-FU/leucovorin and to irinotecan. Therefore, the second specific aim of this proposal is to measure properties of three enzymes associated with the action of these drugs (thymidylate synthase expression, carboxylesterase activity, and topoisomerase I expression and activity) in fresh tumor samples from patients to be treated with the 5-FU/leucovorin/irinotecan chemotherapy outlined above seeking a correlation with response to therapy. Taken together, these aims seek to develop an effective therapy for colorectal cancer and to identify tumor characteristics that may predict which patients are most likely to respond to this regimen.